创伤早期激活的caspase-12引起心肌细胞凋亡及继发性心脏损伤（英文）

发布时间：2018-04-25 23:16

本文选题：创伤 + 心脏损伤　；参考：《生理学报》2017年04期

【摘要】：创伤引起的继发性心脏损伤(trauma-induced secondary cardiac injury,TISCI)是创伤致死的重要原因。本研究组前期研究观察到创伤可以导致心肌细胞凋亡和继发性心功能受损,但具体机制不清。本研究旨在观察创伤时心肌细胞凋亡发生的时间规律,并探讨创伤导致心肌细胞凋亡的可能途径。采用Noble-Collip鼓制备创伤大鼠模型;利用创伤后血清培养正常大鼠心肌细胞48 h。在不同时间点检测心肌细胞凋亡、心脏功能及凋亡相关蛋白酶caspase-3、-8、-9和-12。结果显示,继发性心功能受损出现在创伤后24 h,而创伤大鼠心肌凋亡指数和caspase-3活性均在创伤后6 h就显著增加,12 h达峰值。大鼠心肌组织caspase-12(介导内质网应激反应性凋亡途径)活性和表达在创伤后3 h出现明显升高,6 h达峰值;而心肌组织caspase-8(介导外源性凋亡途径)和caspase-9(介导内源性凋亡途径)均于创伤后24 h激活。同时,采用创伤血清培养正常大鼠心肌细胞,结果同样显示,创伤血清可以引起正常大鼠心肌细胞caspase-3活性显著增加,且心肌细胞caspase-12的活化早于caspase-3、-8和-9的激活;给予caspase-12特异性抑制剂Z-ATAD-FMK处理后,创伤血清引起的心肌细胞凋亡显著降低。此外,创伤后6 h心肌组织caspase-12活性的增高与创伤后24 h继发性心功能减低呈现显著的负相关。本研究表明,在TISCI时caspase-12最早激活,且激活的caspase-12是创伤所致心肌细胞凋亡的重要原因,因此抑制caspase-12介导的细胞凋亡有望成为减轻TISCI的新举措。
[Abstract]:Trauma induced secondary cardiac injury (TISCI) is an important cause of death from trauma. Our previous study found that trauma can lead to cardiac myocyte apoptosis and secondary cardiac function damage, but the mechanism is unclear. The purpose of this study was to observe the time of myocardial cell apoptosis after trauma and to explore the possible pathway of myocardial cell apoptosis induced by trauma. Noble-Collip drum was used to establish traumatic rat model, and normal rat cardiomyocytes were cultured in serum for 48 h. Cardiomyocyte apoptosis, cardiac function and apoptosis-related protease caspase-3-8-9 and-12-12 were detected at different time points. The results showed that the secondary cardiac dysfunction occurred 24 hours after trauma, and the myocardial apoptotic index and caspase-3 activity increased significantly at 6 h after trauma and reached the peak at 12 h after trauma. The activity and expression of caspase-12 (mediated endoplasmic reticulum stress response apoptotic pathway) in rat myocardium increased significantly at 3 h after trauma and reached the peak at 6 h after trauma. Caspase-8 (mediated exogenous apoptosis pathway) and caspase-9 (mediated endogenous apoptosis pathway) were activated 24 hours after trauma. At the same time, normal rat cardiomyocytes were cultured with trauma serum. The results also showed that trauma serum could significantly increase the activity of caspase-3, and the activation of caspase-12 in cardiomyocytes was earlier than that of caspase-3, caspase-8 and -9. After treatment with Z-ATAD-FMK, a specific inhibitor of caspase-12, myocardial apoptosis induced by traumatic serum was significantly decreased. In addition, there was a significant negative correlation between the increase of caspase-12 activity in myocardium at 6 h after trauma and the decrease of cardiac function at 24 h after trauma. This study suggests that caspase-12 is the earliest activation in TISCI, and the activated caspase-12 is an important cause of cardiomyocyte apoptosis induced by trauma. Therefore, the inhibition of caspase-12 mediated apoptosis is expected to be a new measure to alleviate TISCI.
【作者单位】：山西医科大学生理学系;山西医科大学细胞生理学省部共建教育部重点实验室;首都医科大学基础医学院病理生理学系;Blacktown医院重症监护室;山西医科大学附属太钢总医院心胸外科;山西医科大学药理学教研室;
【基金】：supported by grants from the National Natural Science Foundation of China(No.81500185,81341057) the Open Foundation of the Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases of Capital Medical University(No.2014DXWL04) the Science and Technology Innovation Fund(No.057595) 331 Early Career Researcher Grant of Shanxi Medical University,China(No.201402)
【分类号】：R641

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